Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 174, Issue 1, Pages 21-33Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.080620
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Funding
- NCI NIH HHS [CA034282, R01 CA034282] Funding Source: Medline
- NCRR NIH HHS [C06 RR 15490, C06 RR015490] Funding Source: Medline
- NHLBI NIH HHS [R21 HL086706, HL086706, R01 HL082818, HL082818] Funding Source: Medline
- NIAMS NIH HHS [AR49698, P01 AR049698] Funding Source: Medline
- NIDDK NIH HHS [R01 DK060658, DK60658] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA034282] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR015490] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R21HL086706, R01HL082818] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P01AR049698] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK060658] Funding Source: NIH RePORTER
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Recent evidence suggests that subsets of lung fibroblasts differentially contribute to fibrogenic progression. We have previously shown that a subset of rat lung fibroblasts with fibrogenic characteristics [Thy-1 (-) fibroblasts] responds to stimuli (bleomycin, interleukin-4, etc) with increased latent transforming growth factor (TGF)-beta activation, whereas non-fibrogenic Thy-1-expressing [Thy-1 (+)] fibroblasts do not. Activation of latent TGF-beta 1 by interstitial lung fibroblasts is critical for fibrogenic responses. To better understand the susceptibility of fibrogenic fibroblasts to the stimulation of TGF-beta activation, we examined the role of latent TGF-beta-binding proteins (LTBPs), key regulators of TGF-beta; bioavailability and activation, in TGF-beta 1 activation by these fibroblasts. Treatment of fibroblasts with bleomycin up-regulated LTBP-4 mRNA, protein, and soluble LTBP-4-bound large latent TGF-beta 1 complexes in Thy-1 (-) fibroblasts to significantly higher levels than in Thy-1 (+) fibroblasts. Bleomycin-induced TGF-beta 1 activation required LTBP-4, since lung fibroblasts deficient in LTBP-4 did not activate TGF-beta 1. Expression of LTBP-4 restored TGF-beta 1 activation in response to bleomycin, but expression either of LTBP-4 lacking the TGF-beta-binding site or only the TGF-beta-binding domain did not. Bleomycin treatment of mice increased LTBP-4 expression in the lung. Thy-1 knockout mice had increased levels of both LTBP-4 expression and TGF-beta activation, as well as enhanced Smad3 phosphorylation compared with wild-type mice. Together, these data identify a critical role for LTBP-4 in the regulation of latent TGF-beta 1 activation in bleomycin-induced lung fibrosis. (Am J Pathol 2009, 1 74:21-33; DOI: 10.2353/ajpath.2009.080620)
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